Mild hypothyroidism is a heterogeneous and frequent disorder in the general population that is due to autoimmune disease in most of the cases. TSH resistance is considered a rare genetic disease due to germline loss-of-function TSHR mutations. However, TSHR mutations have been mainly searched in patients with large TSH elevations and their actual prevalence among patients with mild TSH elevations (as those found in mild hypothyroidism) is so far unknown. In this study, we evaluated the involvement of TSHR mutations in a large pediatric series of unrelated cases of hyperTSH (n=48, 26 W and 22 M; age 0–12 yrs) selected in various collaborating centers. All subjects had high TSH (4–15 mU/ml), normal freeT4 concentrations, no antithyroid antibodies and normal thyroid volume and structure at ultrasound. Through dHPLC (WAVE apparatus, Transgenomic) and direct sequencing of abnormal PCR products (ABI Prism), we analyzed TSHR coding sequence, proximal promoter and intron-exon boundaries. These investigations lead to the disclosure of 11 carriers of heterozygous TSHR mutations among the 48 patients with hyperTSH (frequency: 22.9%). Seven of these 11 carriers had at least another first-degree relative with known hyperTSH and 4/11 were positive at neonatal TSH screening. Three TSHR mutations are novel (P162L, T607I, R609Q), never found in other patients with TSH resistance and in 150 internal control alleles, and 4 mutations had been previously reported (C41S, P162A, L467P, 655delAC). The mutations C41S, P162A, T607I, 655delAC have been found in 2 unrelated cases. In conclusion, the prevalence of heterozygous TSHR mutations in a pediatric series of hyperTSH is surprisingly elevated. The diagnosis of TSH resistance by means of TSHR gene analysis retains a primary role for appropriate clinical management of subjects with hyperTSH and genetic counseling of their families.
|Titolo:||Prevalence on inactivating TSH receptor (TSHR) mutations in a large series of pediatric subjects with non-autoimmune mild hyper-thyrotropinemia (hyperTSH)|
CORDELLA, DANIELA (Primo)
PERSANI, LUCA (Ultimo)
|Settore Scientifico Disciplinare:||Settore MED/13 - Endocrinologia|
|Data di pubblicazione:||2007|
|Appare nelle tipologie:||01 - Articolo su periodico|